Browse the evidence

Elevated plasma Branched-Chain Amino Acids (BCAAs) are associated with insulin resistance and type 2 diabetes risk, though genetic evidence suggests insulin resistance may drive BCAA levels rather than the reverse.

High levels of BCAAs in your blood are a strong indicator of insulin resistance and future diabetes risk. Interestingly, genetic studies suggest that your body's inability to clear BCAAs (due to insulin resistance) causes the high levels, rather than the BCAAs causing the resistance. If you are insulin resistant, focus on improving metabolic health through diet and exercise rather than just supplementing BCAAs.

DL001 reduces the immunosuppressive effects of mTOR inhibition compared to rapamycin, specifically preserving more T cell and Treg populations.

This study shows that DL001, a selective mTORC1 inhibitor, causes less suppression of T cells and T regulatory cells than standard rapamycin in mice. This suggests that future human applications of selective mTOR inhibitors might have a better safety profile regarding immune function and infection risk, though human trials are needed to confirm this.

Bone marrow adipose tissue (BMAT) is functionally distinct from white and brown adipose tissues, exhibiting high basal glucose uptake but resisting insulin- and cold-stimulated glucose uptake.

Bone marrow fat is not just inert storage; it is a metabolically active tissue that consumes significant glucose at rest but does not respond to insulin or cold like other fats. This suggests that managing overall metabolic health involves factors beyond just visible subcutaneous or visceral fat, and that bone marrow fat may play a larger role in systemic glucose regulation than previously assumed.

SGLT-2 inhibitors produce modest weight loss (2.1-2.7 kg) in people with Type 2 Diabetes by inducing glucose-mediated osmotic diuresis, but are not yet approved specifically for obesity treatment.

SGLT-2 inhibitors (like Jardiance or Forxiga) are used for Type 2 Diabetes and cause modest weight loss (2-3 kg) by peeing out glucose. They are not approved for obesity treatment in non-diabetics, and the weight loss is less significant than with GLP-1 drugs.

Metabolomic biomarkers, particularly Branched-Chain Amino Acids (BCAAs), aromatic amino acids, and specific lipids (ceramides, sphingomyelins), can predict the onset and progression of Metabolic Syndrome and Type 2 Diabetes before clinical symptoms appear.

Current standard blood tests may miss early metabolic dysfunction. Emerging research shows that specific amino acids and lipids rise before diabetes symptoms appear. Until these tests are routine, focus on early lifestyle changes if you have risk factors like central obesity.

Circadian misalignment induces a gene expression profile in skeletal muscle that favors fatty acid metabolism over glucose metabolism, potentially leading to substrate competition and reduced insulin sensitivity.

Your muscles change how they use fuel based on your schedule. When you are misaligned (e.g., working nights), your muscles switch to burning more fat and less glucose, which can interfere with insulin's ability to store glucose. This is driven by changes in gene expression. Maintaining a consistent schedule helps keep your muscle metabolism balanced.

Hepatic lipid accumulation acts as a primary driver of systemic metabolic dysfunction by serving as ligands for PPARs, which upregulate gluconeogenic, lipogenic, and ketogenic genes, thereby promoting hyperglycemia and hyperlipidemia.

If you have fatty liver, your liver is actively contributing to your metabolic issues (like high blood sugar) by sending chemical signals that tell your body to produce more glucose and store more fat. Treating the fatty liver is not just about removing fat; it is about stopping these active signals that drive systemic disease.

The typical hormonal environment in fatty liver disease—hyperinsulinemia, hyperglucagonemia, hypercortisolemia, and growth hormone deficiency—synergistically encourages further hepatic steatosis by dysregulating adipose lipolysis and hepatic lipid handling.

Your body's hormone levels (insulin, cortisol, glucagon) are not just bystanders in fatty liver; they actively drive more fat into the liver. Addressing insulin resistance and stress is key to breaking this cycle.

Obesity causes a shift in HDL subclass distribution from large, protective HDL2 particles to small, dense HDL3 particles, and impairs HDL functionality, including reduced cholesterol efflux capacity and anti-inflammatory properties.

Obesity doesn't just lower your HDL cholesterol number; it makes the HDL you have less effective at protecting your heart. This happens because excess fat increases enzymes that break down HDL and reduces protective proteins like adiponectin. To counter this, focus on weight loss and reducing inflammation, as these changes can restore HDL function and shift the balance back to more protective HDL particles.

Obesity creates a pro-inflammatory environment in white adipose tissue that impairs signaling of fibroblast growth factor 21 (FGF21) by downregulating its co-receptor β-Klotho, leading to FGF21 resistance.

In obesity, the body's natural fat-burning signals (like FGF21) get blocked by inflammation. This means that simply having high levels of these hormones doesn't work; the fat cells stop listening. Reducing inflammation may be necessary to restore these fat-burning pathways.

Central serotonergic signaling acts as an anorexigenic mechanism in the homeostatic circuitry by integrating metabolic signals to suppress food intake when energy needs are met, whereas peripheral serotonergic signaling promotes energy absorption and storage.

Your brain uses serotonin to decide when to stop eating. This process happens in specific brain areas that listen to your body's energy signals. If this system is disrupted, you might eat more than you need, contributing to weight gain. Understanding this helps explain why some medications affecting serotonin can impact weight.

Obesity is associated with disturbed serotonergic signaling, specifically decreased central serotonin release and altered receptor availability, which may contribute to the failure to suppress food intake.

In obesity, the brain's serotonin system often becomes less sensitive or releases less serotonin, making it harder to feel full. This biological change can drive overeating. Treatments that target this system (like certain drugs) may help restore this signaling.

Selective serotonin reuptake inhibitors (SSRIs) are associated with an increased risk of long-term weight gain, contrasting with their short-term anorexigenic effects.

If you take SSRIs, be aware they may contribute to weight gain over time. Talk to your doctor about monitoring your weight and discussing alternative treatments if this is a concern.

Shorter leukocyte telomere length (LTL) is associated with a significantly higher risk of all-cause mortality and cardiovascular disease (CVD).

Your blood test's telomere length isn't a destiny, but a status report. Shorter telomeres correlate with higher heart disease and mortality risk. You can influence this trajectory by managing stress, exercising regularly, maintaining a healthy weight, and avoiding smoking, as these factors are linked to slower telomere shortening.

Historical weight-loss drugs (Thyroid hormones, DNP, Amphetamines) failed due to narrow therapeutic windows and severe adverse effects, despite some efficacy.

Historical weight-loss drugs like DNP, thyroid extracts, and amphetamines were largely withdrawn or restricted due to severe side effects (cataracts, heart issues, addiction) and limited efficacy (<10% weight loss). Their failure highlights the need for safer, more effective modern therapies like polyagonists.

Flavin Monooxygenase 3 (FMO3) activity promotes dyslipidemia and atherosclerosis by regulating hepatic lipogenesis, gluconeogenesis, and impairing transintestinal cholesterol export (TICE).

FMO3 is an enzyme that not only processes nutrients into TMAO but also directly regulates how your liver handles fats and sugars. High FMO3 activity is linked to worse lipid profiles and increased atherosclerosis risk. This regulation happens through complex gene signaling (FXR, LXR, PPARa) that controls cholesterol export and fat storage.

Low serum levels of IGF-I are associated with the severity of NAFLD, including inflammation, hepatocyte ballooning, and fibrosis, even in non-GHD patients.

If you have NAFLD, your IGF-I levels might be low, which correlates with more severe liver damage. While this doesn't mean you should take IGF-I supplements (which are not standard), it highlights the importance of the GH-IGF-I axis in liver health.

Calcium supplementation (≥1,000 mg/day) increases the risk of cardiovascular events, including myocardial infarction and coronary heart disease, particularly in men and postmenopausal women.

If you are taking calcium supplements, especially doses over 1,000 mg per day, be aware that this may increase your risk of heart disease, particularly if you are a man or postmenopausal woman. Prioritize dietary calcium sources, which do not appear to carry this risk, and consult your doctor about your specific cardiovascular risk profile before continuing high-dose supplementation.

In obese individuals, systemic inflammation drives a shift in tryptophan metabolism toward the kynurenine pathway (increased KYN/TRP ratio) and away from serotonin and microbial indole production, correlating with higher inflammatory markers.

This research highlights that obesity is linked to specific changes in how your body processes tryptophan, shifting it away from serotonin production and toward inflammatory pathways. While this paper does not offer a direct intervention, it suggests that managing systemic inflammation and gut health (via diet and lifestyle) may be key to normalizing these metabolic pathways.

SGLT2 inhibitors lower blood glucose in Type 2 Diabetes by blocking renal glucose reabsorption, resulting in increased urinary glucose excretion without causing hypoglycemia.

If you have Type 2 Diabetes, SGLT2 inhibitors are a class of medication that helps your kidneys remove excess sugar through urine. This lowers blood sugar and can help with weight loss, without the risk of dangerously low blood sugar (hypoglycemia) common in other treatments. Be aware of a higher risk for urinary or fungal infections.

Metformin reduces fasting plasma glucose by inhibiting hepatic gluconeogenesis via AMPK activation and reducing free fatty acid plasma concentration.

Metformin is the most common first-line medication for Type 2 Diabetes. It works by reducing the amount of sugar your liver makes and improving your body's sensitivity to insulin. Common side effects include stomach discomfort, which often improves over time.

Epicardial adipose tissue (EAT) and myocardial steatosis contribute to cardiac dysfunction and atrial fibrillation through lipotoxicity, involving the accumulation of diacylglycerols and ceramides.

Managing overall body fat and metabolic health helps reduce epicardial fat, which may lower the risk of heart rhythm issues and heart failure.

Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and a cardiovascular risk factor, driven by lipotoxicity rather than triglycerides alone.

Treating NAFLD requires addressing the underlying metabolic dysfunction and reducing toxic lipid metabolites, not just lowering liver fat content.

Weight loss interventions do not reduce miscarriage rates in overweight and obese women, despite improving pregnancy rates.

While losing weight can help you get pregnant, it does not appear to lower your risk of miscarriage. Focus on the benefits of improved pregnancy rates and overall health rather than expecting weight loss to prevent pregnancy loss.